US20070027198A1 - Crystal of heterocyclic compound - Google Patents

Crystal of heterocyclic compound Download PDF

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Publication number
US20070027198A1
US20070027198A1 US10/571,368 US57136806A US2007027198A1 US 20070027198 A1 US20070027198 A1 US 20070027198A1 US 57136806 A US57136806 A US 57136806A US 2007027198 A1 US2007027198 A1 US 2007027198A1
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crystal
compound
methyl
crystals
powder
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Takeshi Okadai
Kazufumi Nakamura
Tetsuji Harabe
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to crystals of 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]butyl]-1,3-dioxane-r-2-carboxylic acid (hereinafter referred to as Compound A).
  • Compound A 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]butyl]-1,3-dioxane-r-2-carboxylic acid
  • Compound A has blood triglyceride-lowering and low-density lipoprotein cholesterol ⁇ hereinafter referred to as LDL-C) lowering effects as well as blood sugar-lowering or blood insulin-lowering effect or high-density lipoprotein cholesterol (hereinafter referred to as HDL-C) increasing or arteriosclerosis index [a ratio of non-high-density lipoprotein cholesterol to HDL-C, calculated from (total cholesterol value ⁇ HDL-C value)/HDL-C] lowering effect.
  • LDL-C blood triglyceride-lowering and low-density lipoprotein cholesterol ⁇ hereinafter referred to as LDL-C) lowering effects as well as blood sugar-lowering or blood insulin-lowering effect or high-density lipoprotein cholesterol (hereinafter referred to as HDL-C) increasing or arteriosclerosis index [a ratio of non-high-density lipoprotein cholesterol to HDL-C, calculated from (total cholesterol value ⁇ HDL-C value)/HDL-C]
  • Compound A can be prepared according to the following process (for example, see Patent Document 1).
  • Compound A had been prepared in high purity from Compound 1, a synthetic intermediate, by purification by column chromatography and subsequent hydrolysis.
  • the use of column chromatography in purification of a large quantity of synthetic product on an industrial scale necessarily requires use of a great deal of silica gel and a solvent or solvents, which greatly increases the production cost and gives an environmentally adverse effect caused by the solvents used.
  • an alternative process for producing Compound A has strongly been desired, also in view of the complicated and troublesome operation of the current process.
  • the main purpose of the invention is to provide a new specific crystal of Compound A.
  • the present invention includes the followings.
  • FIG. 1 shows a chart of powder X-ray diffraction spectrum in Form I crystal of Compound A.
  • the vertical axis indicates the peak intensity (cps) and the horizontal axis indicates the angle of diffraction (2 ⁇ [°]).
  • FIG. 2 shows a chart of powder X-ray diffraction spectrum in Form II crystal of Compound A.
  • the vertical axis indicates the peak intensity (cps) and the horizontal axis indicates the angle of diffraction (2 ⁇ [°]).
  • FIG. 3 shows a weight change of Form I crystal of Compound A with the elapse of time in a condition of 93% RH at 25° C.
  • the vertical axis indicates the weight change (%) and the horizontal axis indicates the period of storage (the number of days).
  • FIG. 4 shows a weight change of Form II crystal of Compound A with the elapse of time in a condition of 93% RH at 25° C.
  • the vertical axis indicates the weight change (%) and the horizontal axis indicates the period of storage (the number of days).
  • FIG. 5 shows the change in powder X-ray diffraction spectrum in Form I crystal after standing at 25° C. in 93% RH for 14 days.
  • the vertical axis indicates the peak intensity (cps) and the horizontal axis indicates the angle of diffraction (2 ⁇ [°]).
  • the upper chart shows a powder X-ray diffraction spectrum before storage and the bottom one shows that after storage.
  • FIG. 6 shows the change in powder X-ray diffraction spectrum in Form II crystal after standing at 25° C. in 93% RH for 14 days.
  • the vertical axis indicates the peak intensity (cps) and the horizontal axis indicates the angle of diffraction (2 ⁇ [°]).
  • the upper chart shows a powder X-ray diffraction spectrum before storage and the bottom one shows that after storage.
  • FIG. 7 shows the result of measurement by differential scanning calorimetry in Form I crystal of Compound A.
  • the vertical axis indicates the heat flow and the horizontal axis indicates the temperature.
  • the graphs respectively show the changes at a temperature-raising rate of 5° C., 2° C. or 1° C./minute in order from the top.
  • FIG. 8 shows the result of measurement by differential scanning calorimetry in Form II crystal of Compound A.
  • the vertical axis indicates the heat flow and the horizontal axis indicates the temperature.
  • the graphs respectively show the changes at a temperature-raising rate of 5° C., 7° C. or 10° C./minute in order from the top.
  • FIG. 9 shows the result of measurement by differential scanning calorimetry in Form II crystal of Compound A.
  • the vertical axis indicates the heat flow and the horizontal axis indicates the temperature.
  • the graphs respectively show the changes at a temperature-raising rate of 5° C. or 1° C./minute in order from the top.
  • Form I crystal of Compound A is characterized in that it shows peaks at the angles of diffraction of 4.9°, 13.7°, 15.5°, 18.6°, 19.7°, and 21.0°. Among these peaks, those at 4.9°, 13.7° and 19.7° are particularly characteristic.
  • Form I crystal of Compound A is an important intermediate for preparation of Form II crystal which is useful as drug bulk powder.
  • Form II crystal of Compound A is characterized in that it shows peaks at the angles of diffraction of 12.4°, 13.3°, 17.1°, 20.8°, 22.2°, and 25.9°. Among these peaks, those at 12.4°, 17.1° and 20.8° are particularly characteristic.
  • Form II crystal of Compound A is very stable in a condition of high humidity and also stable in a solvent for recrystallization, allowing the synthesis in large quantities on an industrial scale.
  • Form I crystal can be prepared, for example, as follows.
  • the organic solvent includes preferably aromatic hydrocarbon solvents such as benzene, toluene, and particularly preferred is toluene.
  • the organic solvent may be used, preferably, in the amount of 5 to 30 parts (w/w), more preferably 10 to 20 parts (w/w), and particularly 12 to 15 parts (w/w), for 1 part of Compound A.
  • the heating temperature is variable depending on the kind and the amount of the organic solvent used, and in general it is kept preferably at 60-90° C., and particularly at 70-80° C.
  • the reaction is preferably carried out in an inert gas such as nitrogen and argon.
  • Compound A used in this process may be produced, for example, according to the method as described in Patent Document 1, and preferably used after pre-treatment with active carbon.
  • Compound A can be used in any form of crystals or in an amorphous form.
  • the solution may be filtered.
  • a filter funnel equipped with a warming apparatus.
  • the crystals should be re-dissolved under heating after filtration.
  • the solution is rapidly cooled to deposit crystals.
  • a crystallization apparatus equipped with a warming function for dissolving deposit and a stirrer function for cooling.
  • This step is preferably carried out under an inert gas atmosphere such as nitrogen and argon.
  • Preferred cooling temperature is 0 to 20° C. After reaching the cooling temperature, the crystallization is preferably conducted for a period of 0.5 to 5 hours. In addition, it is appropriate to add Form I crystal as a seed. The seed may preferably be added in an amount of 3-5% by weight for Compound A. Preferred cooling rate is 20-40° C./minute.
  • the deposited crystals are collected by a conventional means such as filtration and centrifugation, and dried.
  • the drying may be carried out under reduced pressure or with a drying agent, and in particular preferably under reduced pressure, for example, at, a temperature of 50-70° C. under pressure below 10 mmHg for a period of 6-24 hours.
  • Form II crystal can be prepared, for example, as follows.
  • the organic solvent includes preferably an alcohol solvent such as methanol, ethanol, and 2-propanol; a carboxylic acid ester solvent such as ethyl acetate and isopropyl acetate; a nitrile solvent such as acetonitrile; and an aromatic hydrocarbon solvent such as toluene; and particularly preferred one is isopropyl acetate.
  • an alcohol solvent such as methanol, ethanol, and 2-propanol
  • a carboxylic acid ester solvent such as ethyl acetate and isopropyl acetate
  • a nitrile solvent such as acetonitrile
  • an aromatic hydrocarbon solvent such as toluene
  • Other operation may be conducted in the same manner as in Form I crystal.
  • the solution is slowly cooled to deposit crystals.
  • the preferred cooling temperature is 0-20° C., particularly 5-10° C. After reaching the cooling temperature, the crystallization is carried out for a period of 0.5 to 5 hours, particularly 2 to 3 hours.
  • the solution is cooled to 60° C., it is appropriate to add Form II crystal as a seed.
  • the seed may preferably be added in an amount of 3-5% by weight for Compound A.
  • Preferred cooling rate is 0.5-5° C./minute when the seed is added, and 0.5-1° C./minute when the seed is absent. Other operation may be conducted in the same manner as in Form I crystal.
  • the operation may be conducted in the same manner as in Form I crystal.
  • Highly pure Form II crystal which is useful as drug bulk powder can be prepared according to the following process for industrial preparation.
  • Compound 1 can be produced in the same manner as the process described in Patent Document 1.
  • the resulting Compound 1 may be hydrolyzed directly without purification by column chromatography (for example, see Patent Document 1) to give Compound A.
  • the resulting Compound A is formed (crystallized) into Form I crystal, which is then recrystallized to give highly pure Form II crystal of Compound A.
  • Form I crystal and Form II crystal may be prepared as mentioned above.
  • Form I crystal of Compound A is an important intermediate in preparation of Form II crystal of Compound A.
  • the powder X-ray diffraction spectra were measured by means of a Rigaku Corporation's RAD-2B (target: Cu; Voltage: 40 kV; current: 20 mA; scanning speed: 4°/minute; measurement error: 2 ⁇ 0.2°).
  • Example 1 and Example 2 The differential scanning calorimetry in Example 1 and Example 2 was made by means of a Perkin Elmer DSC7 (temperature-raising rate: 10° C./minute; the range of measurement: 50° C. (constant temperature 1 minute) ⁇ 180° C.).
  • the differential scanning calorimetry in Experimental Example 4 was made by means of Shimadzu Corporation's DSC-50 (temperature-raising rate: 2° C./minute; the range of measurement: room temperature ⁇ 220° C.).
  • the differential scanning calorimetry in Experimental Example 5 was made by means of a Perkin Elmer DSC7 (for temperature-raising rate of 1° C./minute, the range of measurement: 130° C. ⁇ 160° C.; and for temperature-raising rate of 2, 5, 7 or 10° C./minute, the range of measurement: 120° C. ⁇ 170° C.).
  • Step 1 Production of c-5-[5-acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid
  • the extracted organic layer was successively washed with 137 mL of 1% aqueous hydrochloric acid solution and 128 mL of water, and dried on anhydrous magnesium sulfate to give a toluene solution of the objective compound.
  • FIG. 1 shows a chart of powder X-ray diffraction spectrum of the resulting crystal. It is apparent that Form I crystal shows peaks at the angles of diffraction of 4.9°, 13.7°, 15.5°, 18.6°, 19.7°, and 21.0°. Among these peaks, those at 4.9°, 13.7° and 19.7° are particularly characteristic.
  • FIG. 2 shows a chart of powder X-ray diffraction spectrum of the resulting crystal. It is apparent that Form II crystal shows peaks at the angles of diffraction of 12.4°, 13.3°, 17.1°, 20.8°, 22.2°, and 25.9°. Among these peaks, those at 12.4°, 17.1° and 20.8° are particularly characteristic.
  • Form I crystals and Form II crystals of Compound A approximately 1 g each, were precisely weighed in weighing bottles, which were then kept in a desiccator of 93% RH at 25° C. After the lapse of 3 days, 7 days and 14 days, the weight change was observed to measure the amount of absorbed moisture.
  • the powder X-ray diffraction spectra were measured before and after preservation. The results are shown in FIG. 3 (weight change of Form I crystal), FIG. 4 (weight change of Form II crystal), FIG. 5 (powder X-ray diffraction spectrum of Form I crystal), and FIG. 6 (powder X-ray diffraction spectrum of Form II crystal).
  • Form I crystals As shown in FIG. 3 , an increase of weight by 2.3% caused by absorption of moisture was observed. Further, as shown in FIG. 5 , transformation of crystalline form (from Form I to Form II) was recognized.
  • Form II crystal as shown in FIG. 4 , no change of weight caused by absorption of moisture was observed. Further, as shown in FIG. 6 , no transformation of crystalline form (from Form II to Form I) was recognized, too.
  • Form II crystal is useful as drug bulk powder since it is much more stable than Form I crystal in a highly humid condition and causes no transformation of crystalline form.
  • Form II crystal can be recrystallized from a variety of solvents including toluene and easily prepared. Contrarily, Form I crystal can be prepared only by recrystallization from toluene as solvent.
  • Form I crystals and Form II crystals of Compound A 50 mg each, were weighed and respectively suspended in 1 ml of toluene, and stirred overnight. Thereafter, the crystals were separated by filtration and dried, of which the crystalline form was confirmed by a differential scanning calorimetry. As a result, it became apparent that no transformation of crystalline form occurs in form II crystal after stirring overnight to maintain the original crystalline form before stirring, but Form I crystal is transformed into Form II crystal.
  • Form II crystal is useful as drug bulk powder since it is much more stable than Form I crystal in solvents for recrystallization.
  • thermodynamic stability of the crystal of Compound A was investigated by differential scanning calorimetry.
  • the differential scanning calorimetry was carried out at a temperature-raising rate of 1, 2 or 5° C./minute for Form I crystal of Compound A and at 1, 5, 7 or 10° C./minute for Form II crystal. The results are shown in FIG. 7 (a chart of differential scanning calorimetry in Form I crystal), FIG. 8 and FIG. 9 (a chart of differential scanning calorimetry in Form II crystal).
  • Form I crystal showed only one endothermic peak regardless of the temperature-raising rate.
  • FIG. 8 and FIG. 9 no peak of Form I crystal was confirmed in Form II crystal at a temperature-raising rate of 10° C./minute, but a peak resulting from Form I crystal was recognized as the temperature-raising rate was lower like 7° C./minute and 5° C./minute, and its area became large. The result is much more remarkable at 1° C./minute.
  • Form II crystal of Compound A is stable in a highly humid condition and even in a solvent for recrystallization and can easily be prepared on an industrial scale.
  • Form I crystal is an important intermediate for preparation of Form II crystal which is useful as drug bulk powder.

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US10/571,368 2003-09-12 2004-09-10 Crystal of heterocyclic compound Abandoned US20070027198A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2003320556 2003-09-12
JP2003-320556 2003-09-12
PCT/JP2004/013209 WO2005026160A1 (ja) 2003-09-12 2004-09-10 複素環化合物の結晶

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US (1) US20070027198A1 (ko)
EP (1) EP1666479A1 (ko)
JP (1) JPWO2005026160A1 (ko)
KR (1) KR20060123087A (ko)
CN (1) CN1849317A (ko)
AU (1) AU2004272428A1 (ko)
BR (1) BRPI0414274A (ko)
CA (1) CA2538425A1 (ko)
MX (1) MXPA06002666A (ko)
RU (1) RU2006111451A (ko)
WO (1) WO2005026160A1 (ko)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170122417A1 (en) * 2014-03-20 2017-05-04 Thyssenkrupp System Engineering Gmbh Drive device for driving a tool slide in a folding system

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030166697A1 (en) * 2000-05-26 2003-09-04 Kenji Kuwabara Heterocyclic compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030166697A1 (en) * 2000-05-26 2003-09-04 Kenji Kuwabara Heterocyclic compounds
US6998412B2 (en) * 2000-05-26 2006-02-14 Nippon Shinyaku Co., Ltd. Heterocyclic compounds
US7022723B2 (en) * 2000-05-26 2006-04-04 Nippon Shinyaku Co., Ltd. Heterocyclic compounds
US7030143B2 (en) * 2000-05-26 2006-04-18 Nippon Shinyaku Co., Ltd. Heterocyclic compounds
US7144906B2 (en) * 2000-05-26 2006-12-05 Nippon Shinyaku Co., Ltd. Heterocyclic compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170122417A1 (en) * 2014-03-20 2017-05-04 Thyssenkrupp System Engineering Gmbh Drive device for driving a tool slide in a folding system

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WO2005026160A1 (ja) 2005-03-24
CN1849317A (zh) 2006-10-18
CA2538425A1 (en) 2005-03-24
MXPA06002666A (es) 2006-06-06
JPWO2005026160A1 (ja) 2007-11-08
AU2004272428A1 (en) 2005-03-24
KR20060123087A (ko) 2006-12-01
RU2006111451A (ru) 2006-07-27
BRPI0414274A (pt) 2006-11-07
EP1666479A1 (en) 2006-06-07

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